Existing Drug May Treat the Deadliest Childhood Brain Tumor, Stanford-led Study Finds

A multicenter study has identified an FDA-approved medication that prolongs survival in mice with diffuse intrinsic pontine glioma, a brain tumor that now lacks chemotherapy treatments.

For Release: May 4, 2015

For the first time, scientists have identified an existing drug that slows the growth of the deadliest childhood brain tumor.

The drug restricted the tumor’s growth in a lab dish and improved the survival time of mice that had the tumor implanted into their brains, according to researchers at the Stanford University School of Medicine, in collaboration with colleagues at other institutions. The work is noteworthy because the disease, a brain stem cancer called diffuse intrinsic pontine glioma, is nearly always fatal and lacks an effective treatment.

A paper describing the findings were published online May 4 in Nature Medicine.

“There have been over 200 clinical trials of chemotherapy drugs for DIPG, and none have shown any survival benefit,” said Michelle Monje, MD, PhD, assistant professor of neurology at Stanford and a senior author of the paper. “But those trials were conducted before we knew anything about the unique biology of this tumor.”

While the preclinical data in the new study are encouraging, Monje cautioned that the drug, panobionstat, needs further testing in a closely monitored human clinical trial. The research team is now planning such a trial in children with DIPG. Panobinostat was recently approved by the Food and Drug Administration for treatment of a form of blood cancer.

The drug repairs a portion of the cellular machinery now known to be defective in DIPG tumor cells, the new research showed. “A key thing that is wrong with DIPG cancer cells gets corrected by panobinostat,” said Monje, who also treats DIPG patients in her role as a pediatric neuro-oncologist at Lucile Packard Children’s Hospital Stanford. However, the new data also showed that some DIPG cells develop resistance to the drug, which means it will likely need to be combined with other drugs to achieve the best results in humans. “I don’t think this is a cure, but I do think it will help,” she said.

A devastating diagnosis

DIPG affects 200-400 school-aged children in the United States each year and has a five-year survival rate of less than 1 percent; half of patients die within nine months of diagnosis. Radiation gives only a temporary reprieve from the tumor’s growth. In addition, it is inoperable: It grows through the brain stem, where breathing and heartbeat are controlled, “with the healthy and diseased cells tangled like two colors of wool knitted together,” Monje said.

The tumor has also been difficult to study. Because it is not surgically removed nor is it typically biopsied, for decades researchers lacked DIPG tissue to examine in a lab. That changed about six years ago, when Monje and other scientists began asking patients’ families to consider donating tumors for research after patients’ deaths. As a result, in 2009, a study led by Monje was the first in the world to report establishment of a line of DIPG cells that could be studied in a dish. Recently, researchers have determined that 80 percent of DIPG tumors have a mutation in histone 3, one of the proteins that packages DNA. The mutation damages the regulation of DNA in cells involved in the cancer — a form of epigenetic change.

I don’t think this is a cure, but I do think it will help.

In the new study, the research team screened 16 DIPG cell lines derived from patients’ tumors against 83 possible chemotherapy drugs, exposing cells to small samples of each drug. The drugs were chosen because they were thought to have possible effects against brain tumors and were already used in humans or were being developed for human use.

Of the 83 drugs, only a small number showed promise in slowing tumor cells’ growth. The team tracked six of the drugs’ dose-response relationship on DIPG cells and selected panobinostat for further study. They then confirmed the potency and mechanism of panobinostat against DIPG and showed that it normalized some of the detrimental epigenetic changes in the cells and also decreased the expression of genes associated with cancer cell growth.

The team further demonstrated that, in mice that had DIPG tumors implanted in their brain stems, infusing panobinostat directly into the brain stem slowed tumor growth. They also gave the drug systemically by injecting it into mice with DIPG tumors, and showed that enough panobinostat reached the brain stem to prolong the animals’ survival.

In a dish, DIPG cells that survived initial doses of panobinostat developed some resistance to the drug, the study found. However, the team also found that a chemical called GSKJ4, which had previously been shown to inhibit DIPG cells, worked synergistically with panobinostat, with the two agents counteracting known mechanisms of epigenetic dysfunction in the DIPG cells. Although GSKJ4 is not approved as a drug, the finding raises the possibility of developing combinations of drugs to treat DIPG.

‘The goal is multimodal treatment’

“Clearly, the next step is to find out what we can safely combine with panobinostat to increase its efficacy,” Monje said. In addition to the planned clinical trial, which will test whether panobinostat alone improves survival time in children with DIPG, her team will also screen other drugs in combination with panobinostat. “The goal is multimodal treatment to improve outcomes for children with DIPG,” she said.

The paper’s lead authors are Yujie Tang, PhD, a postdoctoral scholar at Stanford; Catherine Grasso, PhD, a postdoctoral fellow at Oregon Health & Science University; and Nathalene Truffaux, PhD, a graduate student at University of Paris-Sud.

Other Stanford co-authors are postdoctoral scholars Lining Liu, PhD, and Wenchao Sun, PhD; life science research associates Pamelyn Woo, Anitha Ponnuswami and Spenser Chen; and Tessa Johung, a medical student.

Other senior authors are Charles Keller, MD, who was at Oregon Health & Science University when the research was conducted and is now scientific director and interim executive director of the Children’s Cancer Therapy Development Institute in Fort Collins, Colorado; Jacques Grill, MD, PhD, at University of Paris-Sud; and Ranadip Pal, PhD, associate professor of electrical and computer engineering at Texas Tech University.

They collaborated with scientists at Université d’Evry-Val d’Essone in France; Texas Children’s Cancer Center and Baylor College of Medicine; Johns Hopkins University; the National Cancer Institute; VU University Medical Center in Amsterdam; Cincinnati Children’s Hospital Medical Center; the Hospital for Sick Children and the University of Toronto in Canada; Children’s National Health Systems in Washington, DC; and University Hospital of Navarra in Spain.

Funding for the research was provided by The Lyla Nsouli Foundation, the Children’s Oncology Group, the DIPG Collaborative (The Cure Starts Now Foundation, Reflections of Grace Foundation, Smiles for Sophie Foundation, Cancer-Free Kids Foundation, Carly’s Crusade Foundation, Jeffrey Thomas Hayden Foundation, Soar with Grace Foundation), Accelerate Brain Cancer Cures Foundation, CureSearch for Childhood Cancer, and the Team Julian Foundation.

Additional funding was provided by the National Institutes of Health (grant K08NS070926), Alex’s Lemonade Stand Foundation, McKenna Claire Foundation, Connor Johnson Memorial Fund, Dylan Jewett Memorial Fund, Elizabeth Stein Memorial Fund, Dylan Frick Memorial Fund, Abigail Jensen Memorial Fund, Zoey Ganesh Memorial Fund, Wayland Villars DIPG Foundation, Jennifer Kranz Memorial Fund, Unravel Pediatric Cancer, Virginia & D.K. Ludwig Fund for Cancer Research, Price Family Charitable Fund, Matthew Larson Foundation, Godfrey Family Fund in Memory of Fiona Penelope, Child Health Research Institute at Stanford, Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, Etoile de Martin, Foundation LEMOS and Le Defi de Fortunee, Scott Carter Foundation, Semmy Foundation, Department of Defense, Marie Curie (a foundation in the United Kingdom), Spanish Ministry of Health, St. Baldrick’s Foundation and Iron Matt Foundation.

Information about Stanford’s Department of Neurology & Neurological Sciences, which also supported the work, is available at

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